About 30% of drugs that appear on the World Health Organization (WHO) Essential Drug List were reported to be poorly water-soluble, based on the Biopharmaceutics Classification System (BCS). See Kasim, N. A., et al., Molecular properties of WHO essential drugs and provisional biopharmaceutical classification, Molecular Pharmaceutics, 2004, 1(1): p. 85-96. Over 40% of newly developed pharmaceutically active substances have solubility issues. See Lipinski, C. A., Drug-like properties and the causes of poor solubility and poor permeability, Journal of Pharmacological and Toxicological Methods, 2000, 44(1): p. 235-249. The poor dissolution and/or permeability of these drugs often result in low and highly variable bioavailability. A major obstacle of successfully commercializing these compounds is the difficulty of enhancing their dissolution rate and extent of dissolution.
For example, Camptothecin is a well-known, poorly soluble, alkaloid that was first isolated in 1966 from Camptotheca acuminate. Camptothecin shows strong cytotoxic activity and anti-tumor activity. Due to its poor water solubility (2.5 ug/mL), the first clinical trials in the early seventies were performed using CPT as the sodium salt of the hydroxycarboxylate form, with an open E-ring. However, severe and unpredictable side effects hindered further clinical development.
A renewed interest in CPT and CPT derivatives came with the elucidation of their mechanism of action, i.e. inhibition of the nuclear enzyme topoisomerase I. It was also discovered that the lactone ring of CPT is necessary for specific interaction with topoisomerase I and selective antitumor activity. Several derivatives of CPT with improved solubility and lactone ring stability have been synthesized, including irinotecan and topotecan (which have been FDA approved for clinical use in the therapy of colorectal, ovarian and lung cancer), as well as SN-38, 9-Aminocamptothecin, 9-Nitrocamptothecin, GI-147211, Exatecan and Karenitecin. See Table 1. The clinical application of these drugs is, however, limited by their toxic, dose-related side effects, such as myelosuppression, gastrointestinal disorders and stomatitis.
TABLE 1Well-known CPT derivatives. CompoundR2R3R4R5R6Camptothecin—H—H—H—H—HTopotecan—H—CH2N(CH3)2—OH—H—H Irinotecan—CH2CH3—H—H—H SN-38—CH2CH3—H—OH—H—H9-Aminocamptothecin—H—NH2—H—H—H9-Nitrocamptothecin—H—NO2—H—H—H GI-147211—H—OCH2CH2O——H Exatecan—CH3—F—H Karenitecin—H—CH2CH2Si(CH3)3—H—H—H
Furthermore, attempts have been made to selectively bind a biologically active, lactone form of a CPT derivative to HSA, in order to prevent HSA from preferentially binding and stabilizing the inactive carboxy form of the CPT derivative, thereby driving the lactone ring/open-ring carboxy blood equilibrium toward the active lactone ring form. However, these attempts have been only partially successful. For instance, in Z. M. Prijovich et al., Biochem. Pharm. 66 (2003): 1181-1187, 9-Aminocamptothecin glucuronide (9AGC) shows improved stability of the active lactone ring form in blood, reaching equilibrium in blood of about 20% lactone ring form and a blood half-life increased to about 50 minutes.
Accordingly, there is a clear and continuing need to create more soluble forms of poorly soluble drugs, such as camptothecin.